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Fasting stimulates autophagy, mitophagy, stem cell production, detoxification, mitochondrial biogenesis, neurogenesis, and neuroplasticity. Fasting also down-regulates muscle catabolism and up-regulates growth hormones to preserve muscle tissue. Because all of these are crucial for health and youthfulness, but tend to decrease rapidly with age, regular fasting is by far the most effective way to naturally slow down ageing and prolong health.

Autophagy means self-eating but refers to the breaking down and removal of damaged tissues, cells, and cellular component to reuse the molecules of which they are made to build new, healthy cells and tissues.

Mitophagy is the same but for mitochondria. Those damaged and dysfunctional are broken down into their constituents to be made available for rebuilding new ones, which is called mitochondrial biogenesis. Fasting is the most effective way to stimulate autophagy and mitophagy primarily through activation of a special enzyme, Adenosine Monophosphate-activated Protein Kinase, or AMPK for short. Fasting also increases production of nerve growth factor that stimulates the growth of new brain cells, no matter how old you are.

Stem cells have as their main purpose to repair tissues. Stem cell activity is highest in embryos and babies, and steadily decreases with age. Stem cell regeneration is strongly stimulated by fasting, but it’s uniquely related to the burning of fat for fuel, and not to the fasting itself. We know this because genetically switching off fat-burning in fasting mice stops stem cell production.

Detoxification takes place through the release of toxins from tissues. Biological survival mechanisms have evolved to sequester into fat cells chemicals and heavy metals from the bloodstream, and isolate them from damaging more sensitive and biologically active tissued and organs in the rest of the body. When fat cells split open to release the energy stored in the fatty acids they stockpile, these toxins are released into circulation for elimination.

Neurogenesis refers to the making of new neurons (brain cells), and neuroplasticity refers to the creation of new synaptic connections and nerve flux pathways in the neural network of the brain. This is without a doubt one of the most remarkable benefits of fasting.

All of these biological mechanisms have deep evolutionary roots. We know this because they are common to the most complex (and thus most recent), and to much simpler (and thus much older) organisms. It is most likely in these deep evolutionary roots that the remarkable healing power of fasting comes from.

Autophagy, mitophagy, stem cells, and ketones

Fasting stimulates the breakdown dysfunctional proteins and cellular components, the preservation of active muscle tissue, and the rebuilding of new proteins and cells upon refeeding. (Read here an excellent article by Dr Jason Fung on the up-regulation of muscle preservation during fasting.) The acute stress of vigorous exercise, especially of strenuous resistance training, stimulates autophagy in much the same way as fasting does. Both stimulate mitochondrial biogenesis. Does this sound inconsequential to you? It really isn’t.

First, the accumulation of damaged cells and cellular debris can be equated to senescence. And senescence can be equated to death. Or rather, the accumulation of death in the body. Death, in this sense, is not really binary, it’s not like one moment we are alive, and the next we’re dead. It’s much more like we accumulate, over time, dead and dysfunctional cells, dead and dysfunctional mitochondria, dead and dysfunctional organelles. Little by little they accumulate, but there’s a threshold. There’s a point beyond which no more death can be accumulated inside the body. And when that threshold is reached, life can no longer be sustained. This is when we die. We call this ageing. The slowing down of things, the loss of energy, the loss of vitality, the loss of strength and flexibility, and the loss of mental acuity and intelligence. But it is, in reality, nothing other than the gradual the loss of life through the gradual accumulation of death.

Second, mitochondria are the source of all the energy that is produced and made available to the body. The mitochondria in the cells produce ATP (adenosine triphosphate), the energy currency for all cellular operations and transactions. And no matter how you look at it, every last little bit of energy that is needed to do anything at all comes from these mitochondria in the cells throughout the body. A tiny drop or increase in energy production in the mitochondria would result in a massive effect on your strength, speed, endurance, resilience, but also concentration and sharpness of mind. Why?

Because there are around 30 trillion cells, and most have between 1000 and 2500 mitochondria each. That makes tens of thousands of trillions of mitochondria. The average cell uses 10 billion units of ATP per day, which means an average adult needs about 3 x 10^25 units of ATP per day. Now you can imagine what happens if the ATP production per mitochondria drops or increases by a tiny fraction, say of just a thousandth of a percent. Because there are so many mitochondria, the magnitude of the effect would be enormous.

Do you remember the “blues and greens” that Jeremy Renner and the other agents carried in little aluminum cases around their necks in the Hollywood film The Bourne Legacy? Remember how much they enhanced both physical and mental performance? This is what these little pills’ main purpose was: to increase mitochondrial energy production efficiency.

We don’t usually think about it in this way, but we should. Doing so, we would understand how important it is to support the body in cleansing and clearing out damaged tissues and cellular components so that they don’t accumulate. And we would also understand how important it is to support the body in rebuilding new, healthy cells and mitochondria to maintain optimal function for as long as possible.

Stem cells everywhere in the body appear to love fat-burning. Because fasting triggers fat-burning in basically every cell of the body, it also triggers an explosion in stem cells activity. It is this explosion of stem cell activity that powerfully stimulates tissue repair and regeneration throughout the body’s tissues.

Ketones are produced in the liver by transforming free fatty acids into beta hydroxy butyrate and acetoacetate through beta-oxidation. Ketones are the preferred fuel for the brain and heart, because burning ketones to generate energy (ATP) produces much fewer reactive oxygen species (free radicals), and thereby significantly reduces oxidative damage to the muscle cells in the heart and the neurons in the brain. Isn’t that so amazing?

The relationship between nutritional ketosis and fasting is simple: the brain is one of if not the most crucial organ because it regulates and coordinates almost everything that happens in the body; the metabolic activity of the brain can be fuelled by glucose or ketones; as blood glucose concentration drops and thus becomes less abundant, ketone production in the liver increases to ensure an adequate supply of fuel to the brain. Glucose levels naturally drop within a few hours, even after a carbohydrate-rich meal, due to the action of insulin. Fasting lowers and maintains low blood glucose levels over significantly longer periods of time. Therefore, in general, the longer the fast, the more ketones are produced, and the more are in circulation in the bloodstream.

Burning ketones for fuel stimulates the production, within cells, of antioxidants like superoxide dismutase (that transforms the superoxide radical into molecular oxygen and hydrogen peroxide), and catalase (that breaks down peroxide). Both the superoxide radical and the hydrogen peroxide molecule can cause many types of cellular damage if not neutralised or broken down as early as possible. So, the more ketones available, the more cellular superoxide dismutase produced, and the less cellular damage from free radical damage sustained. Isn’t this amazing?

Ketones also stimulate the production of adenine dinucleotide phosphate (NADPH) and NAD coenzyme that recharge antioxidants like glutathione, ubiquinol, and vitamin C to a functional state. Major functions of NADPH include recharging antioxidants; providing electrons for the synthesis of fatty acid steroids, proteins, and DNA; and acting as the substrate for NADPH oxidase (NOX) which plays a key role in immune function.

MCT oil and caprylic acid, both derived from coconut oil, are directly and easily converted to fuel and ketones by the liver to fuel brain and heart, and that will therefore bring your lucidity and clarity of mind and thinking. For this reason, they are excellent supplements to take in the morning and during the first part of the day, but should be avoided in the evening because they can lead to hyper-alertness and interfere with a restful sleep. MCT oil shouldn’t be used in case of liver disease.

Nutritional ketosis improves insulin sensitivity, stimulates fat loss, improves mental clarity, reduces risk of cancer, and increases longevity. It reduces cellular damage and inflammation through much lower free-radical and inflammatory cytokine production. And it also increases cellular and tissue repair by stepping up autophagy, mitophagy, and stem cell activation. All of these benefits are consequences, direct and indirect, of sustained low glucose and low insulin levels, and of the derivation of cellular energy from fats and ketones rather than from glucose. In short, nutritional ketosis is amazingly—actually almost supernaturally—good for you.

Toxins and Detoxification

We are all exposed to many toxic chemicals. No matter where we live, and no matter what we do: mold toxins; heavy metals like Hg, As, Pb, Cd from air, water, and food; arsenic (As) from pressure-treated wood, electronics, herbicides; lead (Pb) from gasoline, water pipes, paints; cadmium (Cd) from fertilizers; copper (Cu) as a by-product of many industrial processes that builds up in soil and water; pesticides and herbicides like glyphosate; PAH (polycyclic aromatic hydrocarbons) produced from the combustion of fossil fuels; BPA (bisphenol A) and phtalates used to make plastics; dioxins and dioxin-like (PCBs) from industrial chemical processes; heterocyclic amines from grilling at high heat; hexane, a neurotoxic chemical used to extract more oil from nuts and seeds (including coconut). The list goes on and on.

These are in the soil, in the food, in the water, and in the air. They are also in the soaps, shampoos, creams, makeup, and the countless number of chemical cleaning agents manufactured and sold the world over that we use in our homes. Obviously, the more of them you avoid direct exposure to the better. Consuming toxin-free food as much as possible, and using the simplest and most natural household and personal care products is an essential first step. But if embryos, as protected as one could ever be deep in a mother’s wombs and behind several layers of protective membranes and mechanisms, are known to accumulate toxins, then what about us?

Most of these chemical toxins are fat-soluble. The biochemical processes that have evolved to transport and isolate environmental toxins, whatever they may be, into fat cells is a remarkable survival mechanism that has without a doubt played an important part in allowing living organisms to evolve over the past 3.5 billion years into increasingly more complex plants and animals. However, the Industrial Revolution led to an explosion of human-made chemicals into the environment the pace of which has never ceased to increase.

Did you know that strawberries contain a fibre called fisetin that help remove and eliminate senescent cells from the body, which is essential for prolonging health? But did you know that they are also some of the most chemically contaminated foods together with spinach, nectarines, apples, grapes, peaches, cherries, pears, tomatoes, celery, potatoes, bell peppers? Among the least contaminated are avocados, sweet corn, pineapple, cabbage, onions, sweat peas, papaya, asparagus, mangos, eggplant, honeydew, kiwi, cantaloupe, cauliflower, and broccoli.

In the past four decades only, more than 85 thousand different chemicals have been released into the environment. And the amount has only increased with time. One of, if not the most dangerous is Monsanto’s infamously well-known glyphosate because it is the most heavily used broad-spectrum herbicide of all time: from 1974 to 2016, soils, waters, plants, and animals have absorbed 1.8 million tons in the US alone, and 9.4 million tons worldwide.

Since 1974 in the U.S., over 1.6 billion kilograms of glyphosate active ingredient have been applied, or 19 % of estimated global use of glyphosate (8.6 billion kilograms). Globally, glyphosate use has risen almost 15-fold since so-called “Roundup Ready,” genetically engineered glyphosate-tolerant crops were introduced in 1996. Two-thirds of the total volume of glyphosate applied in the U.S. from 1974 to 2014 has been sprayed in just the last 10 years. The corresponding share globally is 72 %. In 2014, farmers sprayed enough glyphosate to apply ~1.0 kg/ha (0.8 pound/ acre) on every hectare of U.S.-cultivated cropland and nearly 0.53 kg/ha (0.47 pounds/acre) on all cropland worldwide. (Environmental Sciences Europe, 2016, 28:3)

Our fat cells are the body’s chemical storage facility. The more of them there are, the more chemicals can be stored. The less body fat there is, the less chemicals are stored. And if your storage unit is full, then no matter how hard you try, you won’t be able to add another piece of furniture. This is also true for the body’s chemical storage capacity. This is both good and bad, but for different reasons.

More storage allows the organism to survive and function even in the face of significant chemical contamination. But the more chemicals are stored in the body’s fatty tissues, the more the organism as a whole becomes contaminated, and the less able it becomes to function optimally. A large dose of chemical exposure, say from a chemical leak, would require a large fat storage capacity in order to prevent overwhelming the rest of the body’s organs and systems. In such circumstances, someone with more body fat would be better off than someone with less.

But for most of us, this kind of acute exposure from a chemical accident in our near vicinity is not much of a concern. Moreover, you shouldn’t imagine that because chemical toxins are stockpiled in fat cells to minimise exposure in other tissues that they have no effect. Does burying radioactive waste makes it innocuous? It makes it a lot less dangerous and damaging, that’s for sure. But only in the short term, and to some extent, because the radioactive wastes leak out into the soil and the ground water.

The same is true for the chemicals stored in our fat cells. The storing of them protects us from the major toxic effects of direct and large scale exposures, but there is some leaking of these toxins out into the system, especially over time, and as our storage tanks get full. In general, therefore, this is what we should be concerned about: the low-grade chronic exposure and its long-term effects. And the less fat storage, the less chronic exposure there will be.

Fasting regularly and smartly, is the best way to both clear out the storage tanks, and shrink the overall storage capacity for chemical toxins, thus minimising the amount of leaking taking place on a day-to-day basis. So, here’s what we need to know about this:

The more access to fat stores for fuel, the more toxins are mobilised and released from the tissues. This is what we stimulate in the most efficient manner when we fast, because the body needs to sustain all of its cellular processes by burning fat for fuel. But fat loss releases toxins in bloodstream. And this is good because toxins are mobilised. Detoxification, however, must be supported in order for the toxins to be excreted. Otherwise they are released into circulation and can be very damaging. It is for this reason that water fasting is in general not a great idea: it releases too many toxins too quickly, and offers no mechanisms for bindings and eliminating them.

Once toxins are liberated, they must be bound to something in order to be eliminated. To be liberated, toxins are first made water soluble by the addition of a hydroxy (OH) radical. This is essential for elimination, but it makes the toxin more reactive. In a second stage, the now water-soluble but reactive toxin, is conjugated by the addition of a methyl, sulfur, or acetyl group, or else of an amino acid like glycine or glutathionine, in order to be made less reactive. After this, it is transported out of the cell to be eliminated through urine, sweat, or stools.

The detoxification process is supported by facilitating urination (drinking more); facilitating passive sweating (sauna, near-IR is best); eating cruciferous vegetables (broccoli, cauliflower, cabbage, Brussel sprouts, and kale); and supplementing with toxin binders (activated charcoal, chlorella, chitosan, psyllium husks, and citrus pectin). Actually, fat regain following fat loss, something which is very common, is almost certainly a protective mechanism to sequester the toxins that were released but not eliminated. And sweating has to be passive, because exercise suppresses detoxification: the system can be either in fight-or-flight or in rest-and-repair mode; exercise is associated with the former.

Effective detoxification depends on healthy intestinal function. A compromised gut lining allows toxins from the foods or process of digestion to enter the bloodstream. This leads to chronic inflammation and a chronically triggered immune system that eventually results in autoimmune conditions. Fasting reduces gut permeability by enhancing integrity of gut lining: it induces a metabolic switch to fat-burning in the intestinal stem cells that significantly enhances their function, and promotes the healing of the junction between gut lining cells, as well as gut flora diversity.

Resistant starches are good because they feed the gut bacteria, and do not break down into glucose. They are found in under-ripe bananas, papayas, and mangos. Most notable is that if rice is cooked with coconut oil, allowed to cool for 12 hours, and reheated, it will increase in resistant starch by a factor of 10! This reduces calories that would be absorbed from the starch going to glucose by 60%! This simple preparation of the rice turns it from a damaging high-sugar food to avoid, into a beneficial prebiotic. Quite amazing, isn’t it?

How to fast: first steps

Now, before going any further, you should not fast if you are underweight or malnourished; pregnant or breastfeeding; or if you have excessively high uric acid levels. Fasting while underweight or malnourished will exacerbate the negative consequences of the malnourishment. Fasting while pregnant or breastfeeding will release toxins that could potentially be highly detrimental to the baby. And because fasting naturally increase uric acid levels due to the process of cellular cleaning, it could, if starting from an already excessively high concentration, be damaging to the organism. Otherwise, fasting will in general be very beneficial.

First, because fasting strongly influences the regulation of the circadian rhythm, and because one of the most important functions of sleep is to clean out the brain from the byproducts and wastes of its metabolic activity during the waking hours, we should never eat during the night, and always allow at the very least three but preferably four to five hours from our last bite to the time we go to bed. This is necessary to set the conditions for a deep, restorative sleep that keeps our brain in good shape. This is true independently of everything else. So, you can start doing this right away without even having to do any prolonged fasting.

Second, in order to avoid a negative impact on your mental and physical performance during the fast, the body should be adapted to using fat for fuel before you start fasting. You will feel shitty otherwise. I have written two articles that relate to this: Keto-adaptation for optimal physical performance and The crux of intermittent fasting. You should read both. It’s important to understand the biochemical and physiological foundations of why we do things in a particular way. Otherwise, we will lack the intellectual understanding on which depends our ability to make informed choices, but also out resolve to see them through.

Third, in order to have a smooth transition to longer fasting periods, you need to increase your fasting window gradually: to gradually increase the time between your last bite in the evening, and your first bite the next day. Let’s say your sleeping schedule is near optimal, sleeping from 22:00-23:00 to 7:00-8:00. Let’s also assume that you make sure you leave 4 hours before going to bed so that you have your last bite of food around 18:00. Everyone should fast for at least 12 hours. That’s the minimum to aim for, and it requires very little effort.

It would be much better to fast for at least 14 hours, in which case you would wait until 9:00 before having any food. A 16-hour fast would bring you to 11:00 for a late breakfast or early lunch. An 18-hour fast would have you eating lunch at 13:00. And a 20-hour fast means you would be having your first meal around 15:00. Take as long as you need to gradually go from the minimum of 12 hours to at least 16, 18, or even 20 hours.

When you can do this, you will know for sure that your metabolism is well fat-adapted, that your liver is producing ketones efficiently to nourish your brain during fasting periods, that the coarsest detoxification has to a great extent taken place during those weeks or months you have been adapting to longer fasting periods, and that you are now ready to extend your fasts to 24 or 36 hours once in a while, or as much as a couple of times a week. It is far more beneficial on the long term to fast for shorter periods of time every day, then it is to fast for a longer time less frequently. Because each time we fast and then refeed, we activate and benefit from the health-promoting and youth-enhancing mechanisms of the body.

Eating protein activates the mTOR (mammalian or mechanistic target of rapamycin) pathway, which is a powerful catabolic (tissue breakdown) that raises blood sugar levels. Hence, in general, we should keep protein intake to the optimal minimum for our needs. That’s something like this:

Young: 1g/kg of lean body mass per day

Older: 1.2g/kg of lean mass per day

Athletes: 1.5g/kg of lean mass per day

It’s important to remember that beyond the minimum optimal amount, protein intake should be adapted to level of activity: more activity means more protein, and less activity means less protein. Once you are well fat-adapted—after about 8 weeks on a very low carbohydrate diet—you should make a point of having a high fruit and/or starch day once a week. This will ensure that you maintain metabolic flexibility and a perky insulin response. Long term nutritional ketosis can lead to a sluggish insulin response, higher-than-optimal glucose levels and thus glycation, and otherwise unwanted biochemical and hormonal adaptations, which will prevent fat-loss and promote muscle breakdown. Variety stimulates metabolic flexibility.

But make sure it’s clear to you what this means: it means staying in nutritional ketosis for at least 5 days per week. And having a high-carb day means having between 100 and 150 g of sugar/starch from fruit, sweet potatoes, or rice. You should also make that high-carb day a low-fat day. In addition, digestion quality must remain your top priority. This means having your fruit or starches on their own as much as possible, and avoiding combining them with a lot of protein, which will compromise the digestion of both.

How to fast: specifics of keto-fasting

Very importantly, clearance of damaged cells and cellular debris or damaged organelles takes place during fasting, but rebuilding of organelles, cells, and tissues, most notably liver rejuvenation, occurs during refeeding.

Ketofasting following Dr Joseph Mercola’s method is partial fasting lasting ideally around 24 to 36 hours and up to 48 hours. It starts after the last meal of the day, extending over the course of the day following that, either ending with a meal 24 hours later; extending through a second night and ending at the start of the next day for the 36 hour fast; or extending 48 hours to latter part of the day. We saw why water-fasting is not something most of us should be doing in this day and age, and why it’s important to support the detoxification process while fasting. This requires some inputs: it requires protein (amino acids), mitochondrial support, and toxin binders.

The notion of breaking a fast is often taken as binary: we are either fasting or we are not. To some extent this is true. But in many ways it is not. It depends a lot on what it is that we ingest. The essential point is that the benefits of fasting come from maintaining very low blood sugar levels, remaining in nutritional ketosis, and therefore keeping the body in a cleanse-detoxify-repair mode.

Hence, there is a big difference between ingesting a teaspoon of coconut oil or a teaspoon of honey: both provide some calories, but the former supplies only fatty acids that actually promotenutritional ketosis, while the later supplies only simple carbohydrates that will immediately raise blood sugar levels and suppress ketosis, albeit temporarily, and more or less, depending on several other factors defining the body’s metabolic state and efficiency. So, in this regard, it’s better to think of fasting as grey rather than strictly black and white. Naturally, it’s really not an issue to have cucumber and celery with salt, for example.

Protein intake, needed to support the detoxifications processes, should be about half of your daily requirement, for example, 45 g instead of 90 g for 60 kg of lean body mass exercising 3-4 per week. During fasting, protein should not be branched-chain amino acids (BCAAs) nor animal protein rich in BCAAs, because they activate the mTOR pathway that inhibits autophagy. The rest of the calories should be from fat to reach 300-600 kcal from coconut oil, MCT oil, or caprylic acid. Even small amounts of 85% chocolate for which each 10 g square provides 5.3 g of fat, 0.8 g of protein, and 1.5 g of sugar, amounting to 62 kCal of which 48 are from fat, 3.2 from protein, and 6 kCal are from sugar. These are all considered supplemental levels.

In fact, because the purpose of eating protein is to supply amino acids in support of basic functions and detoxification, it is most effective to replace protein intake by an amino acid supplement. And because converstion of protein to amino acids is at most 1/3 efficient, meaning that the highest quality animal protein (e.g., beef) will yield at most 1/3 of its amino acid contents once digested, we can replace 45 g of protein by 15 g of amino acids. Splitting this intake into 4 doses of 4 g each makes for a good rhythm of taking these every couple of hours over 8 hours or so. And they can be taken together with the chlorella and spirulina supplements as well as the phospholipids.

Even though exercising suppresses hunger due to the increase of stress hormones, unfortunately, it also suppresses detoxification. For this reason, you shouldn’t do strenuous exercise on fasting days. Focus on rest and repair.

Phosphatidylcholine and broad spectrum phospholipid to support rebuilding and thereby eliminating chemicals from cell membranes, especially in the brain.

Probiotics (not dairy-based) to help rebuild/balance gut flora if digestion is suboptimal. Keep in mind that the natural flora of the gut is adapted and adapts according to food and drink intake, as well as to the daily rhythms.

Bitters to support the liver in cleansing and elimination (e.g., Dr Shade’s Liver Sauce by Quicksilver Scientific; Swedish Bitters by Flora or by Maria Treben; herbs like Gentian, Dandelion, Goldenrod, Myrrh.)

Binders to support elimination of toxins, all to be taken on an empty stomach to not interfere for nutrient absorption in the gut:

Psyllium husks (1 tbs 1-2 times/day) stirred into a large glass of water—binds to stuff in gut to eliminate in stools;

Chlorella—binds and removes Hg, but also provides a balanced plant protein.

Refeeding is as important as fasting, because this is when the rebuilding takes place. It is very important to remember that. Unless you are overweight and carrying around a lot of energy reserves in the form of extra body fat, intermittent fasting is not a matter of replacing three meals with only one. You need to provide the body with all the energy, macro and micro nutrients it needs to thrive. This remains true under all circumstances. Therefore, you need to make sure to not fall into the trap of eating 1/3 of what you normally would, and grow thinner and thinner with time. That is not the point, and is obviously not sustainable in the long term. You need to provide the bodymind all the nutrition and calories it needs. The key is that this is true on average: If you don’t eat for extended periods of time, you naturally need to eat more when you do.

Concluding remarks

As time goes on and as our technological means of detailed investigations at the cellular level improve, we discover more and more amazing health-enhancing mechanisms through which fasting acts on the organism to make it stronger, more resilient, more functional, and more youthful.

But beyond all the super cool details about the mechanisms by which fasting works its magic on our body and brain, the essential message here is that fasting is really good for us. It’s in fact so good that it’s amazing. And considering that it can stimulate the growth of new mitochondria and even new brain cells, we could even say that it’s miraculously good for us.

Having understood that it is the combination of the fasting period and the refeeding that follows which makes the magic happen, the natural question is how can we maximise this. And the answer is quite simple: we fast and refeed frequently. We fast long enough to activate the health-enhancing cleansing, detoxification, and preservation mechanisms and pathways, and refeed with the most nutrient dense and nutritious foods to maximise the efficiency and effectiveness of the rebuilding and renewal mechanisms and processes.

Once well keto-adapted, and after a period of gradual adaptation to longer fasts, it becomes very easy, and even natural, to fast daily from 18:00 to 12:00 or even 14:00. It even becomes easy and natural to eat two small meals or a single large meal just once a day. In this way, we can get the benefits of fasting and refeeding every single day. Of course, longer fasts of 2, 3, or 4 days will go deeper in stimulating the cleansing, preservation, and repair potential of the fast. But the longer the fast, the more difficult it grows to maintain, and the less frequently it can be done because the rebuilding in between fasts must also be longer. After all, our daily requirements for calories and nutrients is what it is, and although we can easily postpone providing the organism what it needs to function optimally for some time, everything it needs must eventually nevertheless be provided.

This is therefore what I do. A daily fast of about 16 to 20, and usually 18 hours. Once or twice a week a full day’s fast with a single large meal, but typically one small meal around 14 and one larger one around 17 or 18. A comprehensive daily supplement programme; bitters over extended periods a couple of times a year; binders like psyllium husks semi regularly according to need based on quality of bowel movements, and smell of underarm sweat; maximum hydration and alkalisation of body fluids during the fast; and most fundamentally, maximum nutrition at refeeding. Maximum nutrition and nutrient density from plant foods, and maximum nutrition and nutrient density from animal foods. And the final note I’d like to leave you with is this:

The process of ageing is the process of dying. And this process of ageing and dying is a very slow and gradual process of accumulating dead and dysfunctional cells, mitochondria, organelles, and tissues. As these accumulate, we age and die. The faster they accumulate, the faster we age and die. The more we have accumulated, the closer we are to the end, to the threshold beyond which the organism cannot sustain its activity. Fasting—and this is the single most essential benefit of fasting—is by far the most effective way to slow down, minimise, prevent this continuous accumulation of death, and instead promote and stimulate cleansing, renewal, and rejuvenation within this organism that we call our bodymind.

I hope all of what we saw here together will help you enhance your health, and improve the quality of your life.

Of the most remarkable discoveries of the last 15 years, discoveries that might well turn out to be the most remarkable of the 21st century, are those of the telomere—a little tail at the end of our DNA whose length tells us how long we have left to live, and of the enzyme telomerase—the specialised protein whose job it is to try to repair the telomeres so that the cells (and we) can live longer and, from an evolutionary perspective, increase the probability that we’ll have more babies. This and other research into the biology of ageing and the details relating to the transcription of DNA, and the expression or suppression of genes is truly amazingly fascinating. I will turn to this in time, but think it would be jumping the gun to do so now.

What is definitely one of the most remarkable discoveries of the 20th century pertains to the hormone insulin. I am not, however, here referring to the fact that its discovery revolutionised medicine by allowing the saving of countless diabetics from highly premature and painful deaths, usually preceded by torturous amputations of their feet or legs and all the of the horror and misery brought on by these seemingly barbaric and radically extreme measures. (And don’t for one second imagine that such amputations are a thing of the past: I know for a fact—heard directly from the mouth of a practicing orthopaedic surgeon—that amputations are the reality of his everyday, performing sometimes two in a single day.) I’m not either, at least this time, talking about insulin as the master metabolic hormone that regulates the storage into cells of nutrients circulating in the bloodstream. What I am referring to as one of the 20th century’s greatest discoveries in regards to insulin is that of its role in regulating the rate of ageing.

Something that is almost as remarkable is that we hardly ever hear or read about this. For me, that’s really strange. But whatever, I’m not going to hypothesise and speculate to come up with an explanation for why this is. Insulin as regulator of the rate of ageing is what we’ll look at in this article.

Why do mice live two years but bats fifty? Why do rats live three years, but squirrels fifteen. Why do some tortoises live hundreds of year? Why do the smallest dogs, like Chihuahuas, live about twenty years, while the largest, like Great Danes, live five to seven years only? And why do we, humans, live around 80 years, rarely making it to 90, and very rarely to 100 years of age? It is this line of questioning that triggered in the late 80’s and early 90’s a geneticist working in evolutionary biology to hypothesise, for the first time, that ageing could be genetically regulated, at least to a certain extent.

It was the discovery and subsequent realisation in evolutionary biology at that time, that a large number of fundamental cellular processes and mechanisms regulated by a variety of genetic expressions were common to widely different organisms. The realisation was that because all animal life must necessarily share a common ancestor, it is not only logical that the most fundamental functions of cells and especially of how genes express themselves under the influence of hormones essential for life could be the same, but that it should be, to a great extent, expected to be that way. And even though these considerations may seem obvious in retrospect, the fact is that there was only one person with this knowledge, asking these questions, and having the means to do something about seeking an answer to some. Cynthia Kenyon, Professor at UCSF, was this person.

The subject was quick to choose: the tine worm that Kenyon had already been studying for years, C. elegans, was perfect because it is simple but nonetheless a complex animal, and because it has a short natural lifespan of about 30 days. The first step was clearly defined: find at least one long-lived individual. What seems very surprising from our current vantage point it that she couldn’t readily find one: she couldn’t convince anyone to join with her in this endeavour. Everyone was at that time convinced that ageing was something that just happened: things just wore out and deteriorated with use and with time; nothing to do with genes. But how could this be if different species—some very physically similar—are witnessed to have such widely different lifespans? It just had to be genetic at some level, Kenyon thought. Eventually, after a few years of asking around and searching, she found a young PhD student that was up to it, and set out to find a long-lived mutant.

A number of months down the road a long-lived mutant was found and immediately identified as a ‘DAF-2 mutant’. This mutation made the DAF-2 gene—a gene responsible for the function of two kinds of hormonereceptors on a cell’s membrane—less active. The next step was to artificially create a population of DAF-2 mutants and see how long they live, statistically speaking, compared to normal C. elegans. It was found that the genetically ‘damaged’ worms, the ones for which they had turned down the expression of the DAF-2 gene, lived twice as long: starting with exactly the same number of worms, it took 70 days for the last one of the mutants to die compared to 30 days in the normal population.

But an additional observation was made: the curve that traced the fraction of worms remaining was stretched by a factor of two from about the start of adulthood for the mutants. They had the same relatively short childhood but then for the remainder of their lives, for every day in the life of the normal worms, the mutants would live two days. The most impressive was that they were really half their chronologically equally aged cousins in all respects: external appearance, level of activity and reproduction.

To make your appreciate this point as much as you should, this observation with respect to not just the lifespan but notably the healthspan of C. elegans would translate in human terms in someone being 80 years old but looking and acting like a 40 year old in the sense that nobody could tell that they were not 40, let alone 80 years old. Just like Aragon in the The Lord of the Rings. This person would be like a 40 year old at 80, like a 60 year old at 120, and like an 80 year old person coming to the end of their life by the time they were 160! Can you even imagine that? Hard isn’t it. But this is exactly what Kenyon and her team were looking at in these experiments with these little worms.

Now they wanted to understand the effect of the DAF-2 gene, or rather, understand the effect of suppressing its expression in the DNA of each cell’s nucleus at different developmental stages. If it was turned off completely, the worms would die: clearly, DAF-2 expression, at least in C. elegans, is essential for life. If it was suppressed immediately after birth (hatching), the little worms would enter the Dauer state in which they don’t eat, don’t grow, don’t reproduce, and basically don’t move either: they just sit and wait. Wait for what? For better times!

This Dauer state is a remarkable evolutionary adaptation seem in some species that allows the individual to survive during periods of severe environmental stress such as lack of food or water, but also high UV radiation or chemical exposure, for example, for long periods of time with respect to their normal lifespan in a very efficient kind of metabolic, physiological and reproductive hibernation. What’s really cool is that inducing worms out of the Dauer state, no matter how long they’ve been in it, they begin to live normally again, moving and eating, but also reproducing. So, in the Dauer state C. elegans literally stops ageing altogether and waits, suspending metabolic activities and physiological functions until conditions for reproduction and life become adequate once again.

If DAF-2 expression was turned back up to normal, then they moved out of Dauer and resumed their development stages equivalent to childhood, teenage-hood, and then adulthood, but didn’t live any longer as adults. Finally, suppressing DAF-2 expression at the onset of adulthood resulted in the extended lifespan as originally observed. The conclusion was therefore clear: DAF-2 expression is essential for life and necessary for normal and healthy growth and development in immature individuals from birth until they reach maturity, and suppressing DAF-2 expression was only effective at extending both lifespan and healthspan in mature individuals.Going further, they now wanted to understand how DAF-2 suppression actually worked to extent healthspan: what were the actual mechanisms that made the worms live longer when DAF-2 expression was turned down. For this, Kenyon’s team needed to look at all of C. elegans’s 20000 genes and figure out how they affect each other. (Note that this is also more or less how many genes we have, but C. elegans has only 3 chromosomes and is also hermaphrodite.) The sequencing of the worm’s genome was done in 1998, and what was found after analysis was very interesting:

The DAF-2 gene activate a phosphorylation chain that attaches phosphate groups onto the DAF-16 transcription factor. In normal individuals the DAF-2 gene is expressed normally, the phosphorylation chain works unimpeded, and the DAF-16 transcription factor is inactivated. In the mutants, the DAF-2 gene expression is suppressed, and as a consequence, the DAF-16 transcription factor is not inactivated and instead accumulates in the nucleus. There, DAF-16 encodes what Kenyon’s team showed to be the genetic key to health and longevity they were looking for from the start of this now decade long pursuit: the FOXO gene.

What does FOXO do? It promotes the expression of other genes, at least four other genes: one responsible for manufacturing antioxidants to neutralise free radicals the largest amount of which are produced by the mitochondria as they make energy for the cell, a second responsible for manufacturing ‘chaperons’ whose role as specialised proteins is to transport other proteins and in particular to bring damaged ones to the cell’s garbage collector and recycling facility to promote the replacement of those damaged proteins by new and well-functioning ones; a third responsible for manufacturing antimicrobial molecules that increase the cell’s resistance to bacterial and viral invaders; and the fourth that improves metabolic functions and in particular fat transport (reduce) and utilisation (increase).

It is these four genetically regulated cellular protection and repair mechanisms, the cumulative combined effects of all these increased expressions of antioxidants, chaperons, antimicrobials and metabolic efficiency—all of them at the cellular level—that allow the lucky DAF-2 suppressed mutants to live twice as long twice as healthy. Remarkable!

Now that all the cards about how the long-lived mutants actually live twice as long as expected under normal conditions are laid on the table, and that there is only one detail I left out of the story up to this point, tell me: can you guess what are the two sister hormones to which the cell’s sensitivity through the activity of its receptors for them are controlled by the DAF-2 gene? It’s a trick question because I told you half the answer in the introduction: The DAF-2 gene encodes the hormone receptors for both insulin and the primary form of insuline-like growth factor IGF-1. Surprised? It isn’t surprising, really. In fact, it all makes perfect sense:

Insulin and IGF-1 promote growth; nutrient absorption and cellular growth and reproduction are essential for life and thus common to all living organisms, including the more primitive of them like yeasts; growth in immature individuals is fundamental for health and for ensuring they reach maturity; but growth in adults, in mature individuals, just means ageing, and the more insulin and IGF-1 there is, the faster the rate of cellular damage and deterioration, the more genetic mutations from errors in transcription, the more pronounced the deterioration of the brain and the heart, of the arteries and the veins, of the muscles, the bones and the joints, and obviously, the faster the rate of ageing. Because what is ageing if it is not the word we use to describe the sum total, the multiple negative consequences, the end result of all of these deteriorations in these vital organs and systems but also everywhere else throughout the organism, all of it starting at the cellular level, in the nucleus of every cell.

About the necessity of insulin for normal growth, you should definitely not think that these observations impliy we should stimulate insulin secretion in the young in order to ensure proper growth. Totally not! The body knows exactly when and how much insulin is needed at any given time. In fact, any additional stimulation of insulin promoted by eating simple and starchy carbs actually deregulates the proper balance of hormones that the body is trying to maintain. This deregulation from a sugar laden diet in children is the very reason for many wide spread health problems in our youth most important of which is childhood obesity and the metabolic and physiological stresses this brings on. So, leave it to mother nature to know how to regulate the concentration of insulin in the bloodstream. Do not disrupt the delicate biochemical balance by ingesting refined carbohydrates: it’s the last thing anyone needs for good health and long life.

The first results were so interesting that several other groups joined in this research into the genetics of ageing. Not as much as one would think, but at least a handful of other groups began to apply and expand the techniques to other species. Unsurprisingly, the same effects, although with different magnitudes, were seen in these very different species, from an evolutionary standpoint: fruit flies and mice. In addition, the connection was made with lifespan-extending experiments using calorie-restriction, which have also been carried out on mice and other animals (we’ll look into this another time). And beyond the work around DAF-2, DAF-16 and FOXO, Kenyon’s group investigated other ways to influence lifespan and found two more.

The first was by disabling some of the little worm’s sensory neurones of which there are very few, making it easy to test and determine the influence they have separately and in combinations. They tested smell and taste neurones, found that disabling some would extend lifespan while disabling others didn’t. They also found that disabling different combinations of smell and taste neurones could have nulling effects. The second was playing with the TOR gene expression. For now, however, we will leave it at that.

As the fact that it is rare and relatively hard to come by this work without actually looking for it, there is something else I find very hard to comprehend. In Kenyon’s various lectures on this work, there is usually a mention of the biotech company she founded called Elixir Pharmaceuticals and how they aim to find one or more drugs that can suppress DAF-2 expression in humans without causing negative side-effects in order to extend lifespan and healthspan as was done in C. elegans with genetic manipulation. That’s fine, and does make sense to a certain extent, especially if we can find not chemical drugs but natural plant-derived compounds that have this effect on us.

The thing that doesn’t make sense and that is hard to understand from the naive perspective of the honest scientist looking for the simplest possible solution to a problem of inferring something we don’t know from information that relates to what we want to know: in this case this mean the simplest way to make the best use of this information and apply what we have learnt from these two and half decades of research in a way that we know would be beneficial in promoting a longer and healthier lifespan in humans without risks through the introduction of foreign substances in our body. Because they haven’t, here I offer my attempt to do this.

We have, thanks to Kenyon and others, understood in great detail how lifespan in complex organisms can be, to a great extent, genetically regulated, and which genes, transcription factors and mechanisms are involved in the process of regulating the rate of ageing in conjunction with the propensity for developing age-related degenerative diseases. In the final analysis, the main players are the DAF-2 gene that tunes up or down the sensitivity of insulin and IGF-1 receptors, the DAF-16 transcription factor that encodes the FOXO gene but is made inactive by the expression of DAF-2, and the star FOXO longevity gene that promotes the expression other genes responsible for stimulating the cell’s most powerful protection and repair mechanisms.

We have, from many decades of research on calorie-restriction and fasting in animals including humans (and which we’ll explore elsewhere), understood that this is an extremely effective way to extent both lifespan and healthspan and basically eliminate the occurrence of age-related degenerative diseases by greatly increase resistance to health disorders of all kinds. Some key observations on calorie-restricted animals include their very low blood levels of sugar, insulin and IGF-1, high metabolic efficiency and ability to utilise fat demonstrated by low blood levels of triglycerides, and their remarkably younger appearance with increased energy and activity levels.

And finally, we have, from more than a century of observations and research, concluded that diabetics, whose condition is characterised by very high levels of blood glucose, insulin and triglycerides, are plagued by a several-fold increase in rates of cancer, stroke, heart disease, kidney disease, arthritis, Alzheimer’s and dementia, basically all the age-related degenerative diseases known to us, and in addition, also a several fold increase in their rate of ageing based on the spectrum of blood markers used for this purpose, their appearance, but also on the length of their telomeres.

Is it not, therefore, obvious from these observations that high blood sugar, high insulin and high triglycerides are hallmarks of accelerated ageing and a propensity for degenerative diseases, while low blood sugar, low insulin and low triglycerides are instead necessarily related to extended lifespan, extended healthspan and increased resistance to all disease conditions including those categorised as degenerative, and this, independently of the actual mechanisms involved?

Is it not, therefore, plausible from these observations that the genetic mechanisms relating to the function of the DAF-2 gene, DAF-16 transcription factor and FOXO gene in conferring to the DAF-2 mutants twice as long a life can, in fact, be activated and enhanced epigenetically by creating an environment in the organism that is conducive to it: simply by keeping blood sugar, insulin and triglycerides as low as possible? In other words, isn’t it plausible from these observations that by manipulating the biochemistry to ensure that blood sugar, insulin and triglycerides are throughout the day and night as low as possible depending on the organisms requirements, that this will actually translate into the activation of the FOXO gene to enhance protection and repair at the cellular level and thus extend lifespan and healthspan?

And what is, not only the easiest and simplest, but also the most effective way to do this? It is to eliminate insulin-stimulating carbohydrates—sugars and starches—from the diet completely. This, within 24-48 hours, will allow sugar levels to drop to a functional minimum. The low blood sugar will allow the pancreas to reduce production and insulin levels to drop bit by bit. Lowered insulin will eventually allow the cells to start using the fat circulating in the blood, and in time, increase in efficiency, thereby dropping triglyceride levels lower and lower.

Why is it you think that Kenyon never mentions this anywhere? Do you think that this has simply not occurred to her? I honestly don’t know. But if there is a single thing to remember it is this: insulin is necessary for life; in the immature individual, insulin regulates growth; in the mature individual, insulin regulates the rate of ageing and the propensity for degenerative diseases. Hence, if you are a mature individual, and by this I mean full grown, and if you want to live long and healthy, the very first thing you need to do is to keep the concentration of insulin circulating in your blood as low as possible. Everything else that we can do to extend healthspan and lifespan is secondary to this.

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